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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:3489-3494.)
© 1997 American Heart Association, Inc.

Articles

Bcl I Polymorphism in the Fibrinogen ß-Chain Gene Is Associated With the Risk of Familial Myocardial Infarction by Increasing Plasma Fibrinogen Levels

A Case-Control Study in a Sample of GISSI-2 Patients

Francesco Zito; Augusto Di Castelnuovo; Concetta Amore; Andria D'Orazio; Maria Benedetta Donati; ; Licia Iacoviello

From the Istituto di Ricerche Farmacologiche Mario Negri, Department of Vascular Medicine and Pharmacology, "A. Valenti" Laboratory of Thrombosis Pharmacology, Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy (F.Z., A. Di C., C.A., A.D, M.B.D., L.I.); and Gaubius Laboratory, Leiden, The Netherlands (L.I.).

Correspondence to Licia Iacoviello, MD, Department of Vascular Medicine and Pharmacology, "A. Valenti" Laboratory of Thrombosis Pharmacology, Consorzio Mario Negri Sud, 66030 Santa Maria Imbaro, Italy. E-mail iaco{at}cmns.mnegri.it

	Abstract

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Abstract The aim of this study was to investigate the association of the Bcl I ß-chain fibrinogen polymorphism with the risk of acute myocardial infarction (AMI) and its relationship with fibrinogen levels in the Italian population. We studied 102 AMI patients, selected within the framework of the GISSI-2 trial, who had a familial history of arterial thrombosis (at least one first-degree relative suffering from AMI or stroke before 65 years) and 173 control subjects (with neither AMI nor personal or familial history of arterial thrombosis). All subjects were Italian. Patients showed fibrinogen levels higher than control subjects. There was a highly significant difference in allele frequency in cases versus control subjects, the B2 allele frequencies being respectively 0.28 versus 0.17 (P=.002). In multivariate analysis, adjusted for sex, age, smoking habits, and history of hyperlipidemia, hypertension, or diabetes, the (B1B2+B2B2) genotype was associated with a higher risk of AMI (odds ratio 2.4, 95% confidence interval, 1.2 to 4.6). The Bcl I genotype was also associated with fibrinogen levels, independently of gender and smoking habits, the (B1B2+B2B2) subjects showing the highest levels in both cases and control subjects. The difference in fibrinogen levels between cases and control subjects was significantly influenced by the genotype (significant interaction, P=.042) The B2 allele of the Bcl I polymorphism in the ß-chain of the fibrinogen gene is a new factor associated with the risk of familial AMI through its association with fibrinogen levels. These data provide evidence for a causal role of fibrinogen in familial AMI.

Key Words: fibrinogen • polymorphisms • myocardial infarction • family history

	Introduction

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Cumulative data imply that high fibrinogen levels are an independent risk factor for stroke, coronary heart disease, and peripheral artery disease.^{1 2 3 4 5 6 7 8 9 10 11 12} Recently, genetic control of fibrinogen levels has been suggested. Although several polymorphisms have been described in the genes encoding the fibrinogen chains, the data available until now on their association with blood fibrinogen levels are controversial.^{8 9 13 14 15 16 17 18} Fibrinogen is a large glycoprotein dimer with a molecular weight of 340 000 D; each dimer is formed by three pairs of polypeptide chains, known as A-, B-ß, and -chains, arranged symmetrically. The three genes encoding the three chains are located in a cluster of about 50 kb on the long arm of chromosome 4.^{19 20} Humphries et al^{15 21} demonstrated an association between the Bcl I polymorphism of the ß-chain gene of fibrinogen and fibrinogen levels. In the latter study on 91 English subjects, the B1B1 homozygotes had a mean fibrinogen concentration of 274 mg/dL, the heterozygotes had a concentration of 298 mg/dL, and the homozygotes for the B2 allele had a mean concentration of 369 mg/dL. In a similar study, Berg and Kierulf¹⁶ were not able to confirm these findings in Norwegian subjects.

The possibility that the ß-chain fibrinogen genotype may have an effect on the risk for arterial diseases has also been investigated. In the Edinburgh Artery Study, there was a higher frequency of the B2 allele of the ß-chain fibrinogen gene in patients with peripheral artery disease than in control subjects.⁹ However, there was no correlation found between the polymorphism and blood fibrinogen levels either in patients or in control subjects. More recently, Behague et al¹⁷ studied the impact of several fibrinogen ß-chain polymorphisms on the outcome of coronary artery disease. They found that only the B2 allele of the Bcl I polymorphism was associated with the severity of coronary stenosis, but not with the occurrence of acute myocardial infarction (AMI), suggesting an interaction between this genotype and the development of atherosclerotic complications. ß-Chain formation is the rate-limiting step in the assembly of the molecule, and its genetic modification could be responsible for changes in synthesis and activity of the fibrinogen molecule.²² All together, these data suggest that some genetic variability near the Bcl I ß-chain locus may be involved in the pathogenesis of cardiovascular ischemic disease, although such involvement has never been determined for AMI. The purpose of this study was to investigate the association of the Bcl I ß-chain fibrinogen polymorphism with the risk of AMI and its relationship with fibrinogen levels in the Italian population. We studied a homogeneous sample of Italian AMI patients with a high likelihood of inherited risk, defined by the presence of a family history of thrombosis.

	Methods

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Subjects
One hundred two patients with familial AMI and 173 control subjects were enrolled in this study. Cases were recruited in hospitals participating in the GISSI-2 study,²³ which were spread throughout Italy. These patients had experienced their first episode of AMI and reported having at least one first-degree relative affected by AMI and/or stroke before 65 years.²⁴ The GISSI-2 AMI population with at least one relative with history of thrombotic events represented the 35% of the total number of the patients recruited in the framework of the GISSI-EFRIM.²⁴

One hundred seventy-three control subjects without AMI, stable or unstable angina, stroke, or transient ischemic attacks, were consecutively selected among subjects attending the hospitals for any clinical reason except acute conditions.²⁵ Subjects reporting personal or family history of thrombosis (AMI, stable or unstable angina, stroke, or transient ischemic attack), with defined defects of the hemostatic system, and with chronic liver diseases were excluded. Data were collected by ad hoc trained interviewers, using a structured questionnaire that included personal data, cigarette smoking, and medical history (diabetes, hypertension, hyperlipidemia). Diabetes was considered to be present if the patient was under treatment or considered by the admitting physician to be diabetic. Hypertension and hyperlipidemia were considered only if the patient was under antihypertensive or hypolipemic treatment. All interviewers were trained and checked for reliability and consistency.²⁴ The subjects included in this study were all Italian and were distributed throughout the main Italian geographic areas (north 31%, center 19%, south 42%, and Sardinia 8%, for both cases and control subjects).

This work was performed according to the Declaration of Helsinki of 1975 and was approved by the Mario Negri Sud Ethical Committee.

Blood Samples
Patients were interviewed within 5 to 7 months of their most recent ischemic event. Blood sample collection was performed between 8 and 10 AM, after 20 minutes' supine rest, from subjects who had fasted overnight and had refrained from smoking for at least 6 hours before blood sampling. Patients under oral anticoagulant treatment were excluded.

Venous blood was collected from an antecubital vein without stasis into plastic syringes, added to 3.8% sodium citrate (9:1, vol/vol) in precooled plastic tubes, and kept on ice until centrifugation. Plasma was obtained by centrifugation at 2000g for 20 minutes at 4°C, and aliquots were frozen at -80°C until testing.

Plasma fibrinogen concentrations were assayed by the modified Clauss functional method (Dade, Miami, Fla; MLA 1600; interassay and intra-assay coefficients of variation being 4.7% and 2.9%, respectively).

DNA Extraction and Bcl I Polymorphism Detection
Peripheral venous blood samples were drawn, and white blood cells were separated. DNA was extracted from peripheral blood using standard procedures. Amplification of the ß-chain fibrinogen gene was obtained by polymerase chain reaction followed by gel electrophoresis. Fifty microliters of polymerase chain reaction contained 100 ng genomic DNA, 200 ng of each appropriate primer, 10 mmol/L Tris/HCl, pH 8.3, 1.5 mmol/L MgCl₂, 50 mmol/L KCl, 0.01% (wt/vol) gelatin, 0.1% Triton X-100, 200 mmol/L dNTPs, and 1 U of Taq polymerase (Promega Corporation). Samples were incubated at 95°C for 5 minutes, followed by 30 cycles of 95°C for 1 minute, 55°C for 1 minute, and 72°C for 1 minute. The primers used were (5'-3') ACC TGG TTT CTC TGC CAC AAG (coding strand) and AAT AGT TCT CAT ACC ACA GTG T (noncoding strand).²⁶ Ten microliters of the polymerase chain reaction product was digested with 10 U of the Bcl I restriction enzyme (Promega Corporation) and run by electrophoresis in a 1.5% agarose gel and visualized directly by ethidium bromide staining. Two alleles, B1 and B2, were detected at 2500 bp and 1100+1400 bp, respectively.

Statistical Analysis
Data were analyzed by the Mario Negri Sud mainframe computer with the SAS statistical package. The frequencies of the alleles and genotypes among cases and control subjects were counted and compared by the ² test with the values predicted by assumption of the Hardy-Weinberg equilibrium. ² analysis or Fisher's exact test was used to compare differences between discrete parameters. The differences between cases and control subjects were analyzed by unpaired Student's t test for fibrinogen levels and by the Kruskal-Wallis test for age, according to their observed distribution. Odds ratios (ORs) as estimators of relative risk, together with their 95% approximate confidence intervals (CIs) were computed to assess the association with disease of (B1B2+B2B2) genotype in relation to the B1B1 genotype. Multiple logistic analysis was performed by using LOGISTIC procedure for SAS; confounding variables included were age, gender, smoking habits, history of hyperlipidemia, hypertension, and diabetes. In a separate analysis, the genotype effect on AMI risk was also adjusted for fibrinogen levels. A general linear model (unbalanced ANOVA for two-way design with interaction) was used to assess differences of fibrinogen levels in patients versus control subjects, in B1B1 versus (B1B2+B2B2) individuals, and to assess the interaction between case status and Bcl I genotype. Fibrinogen levels were adjusted for gender and smoking habits.

All the results are given as mean±SD. A value of P<.05 was considered significant.

	Results

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One hundred two patients with familial AMI (with at least one relative with AMI or stroke before 65 years) and 173 control subjects entered the study.

Genotype distributions and B1 and B2 allele frequencies at the Bcl I ß-fibrinogen locus are shown in Table 1. Genotype distribution was in Hardy-Weinberg equilibrium in the control group, whereas it deviated from equilibrium (²=4.3, df=1, P=.04) in the group of AMI patients. The frequency of allele distribution was significantly different in patients versus control subjects (P=.002), the B2 allele frequencies being, respectively, 0.28 versus 0.17. Genotypes were differently distributed between cases and control subjects (P=.002, Fisher's exact test). Because of the low number of B2B2 homozygotes, we considered individuals carrying the B1B2 and B2B2 genotype as only one group (B1B2+B2B2) for further analyses. The genotype frequencies were still largely different between cases and control subjects (P<.001): there was an excess of subjects carrying the B2 allele in AMI patients compared with control subjects (53% versus 32%).

View this table: [in this window] [in a new window]   Table 1. Allele Frequency and Genotype Distribution of Bcl I Fibrinogen Polymorphism in Patients With Familial AMI and in Healthy Control Subjects

The characteristics of the two groups and the relative ORs are shown in Table 2. Cases were slightly older than control subjects and had a higher prevalence of common risk factors for atherosclerotic disease (such as smoking habits, history of diabetes, hyperlipidemia, and hypertension). After multivariate analysis, only age, smoking, and hyperlipidemia remained significantly associated with the risk of familial AMI.

View this table: [in this window] [in a new window]   Table 2. Characteristics of Patients With Familial AMI and Healthy Control Subjects

Patients also showed plasma fibrinogen levels higher than control subjects (310±76 versus 243±50 mg/dL, P<.0001). The OR attributed to the increase of 10 mg/dL in fibrinogen levels was 1.23 (95% CI 1.16 to 1.30) in univariate analysis and was not modified by adjusting for other confounding variables (OR 1.22, 95% CI 1.14 to 1.31).

In univariate analysis, the genotype (B1B2+B2B2) was associated with an increased risk of familial AMI. Compared with subjects with the B1B1 genotype, the OR for subjects carrying the B2 allele was 2.4 (95% CI 1.5 to 4.0). The impact of the B2 allele on familial AMI risk was also confirmed after adjustment for age, gender, smoking habits, history of diabetes, hypertension, and hyperlipidemia (OR 2.4, 95% CI 1.2 to 4.6) and was as strong as the risk determined by smoking and age. Conversely, the association between fibrinogen genotype and familial AMI was lost after adjustment for fibrinogen levels (OR 1.3, 95% CI 0.7 to 2.5).

Fibrinogen levels in cases and control subjects, according to the Bcl I fibrinogen genotype, and the interaction between case status and genotype are shown in Table 3. After correction for gender and smoking habits, the (B1B2+B2B2) genotype was still associated with higher fibrinogen levels in both cases and control subjects. The difference in fibrinogen levels between cases and control subjects was more pronounced in subjects carrying the genotype (B1B2+B2B2) (337±59 versus 262±58 mg/dL) than in that between cases and control subjects with the B1B1 genotype (276±58 versus 232±59 mg/dL), the interaction between case status and Bcl I genotype on fibrinogen levels being significant (P=.042). In the stepwise regression analysis including genotype, age, sex, smoking habits, history of diabetes, hypertension, and hyperlipidemia, the Bcl I genotype accounted for 14% (the model explaining 24% of the variance) and 8% (the model explaining 10% of the variance) of the fibrinogen variance, respectively, in cases and control subjects.

View this table: [in this window] [in a new window]   Table 3. Fibrinogen Levels (mg/dL) in Patients and Control Subjects Associated With Bcl I Genotype

	Discussion

Top Abstract Introduction Methods Results Discussion Appendix 1 References

 
We report here the first evidence that the presence of the allele B2 of the ß-chain fibrinogen gene is independently associated with both an increased risk for familial AMI and increased plasma levels of fibrinogen. Moreover, the influence of genotype on risk of AMI is mainly due to its effect on fibrinogen levels.

Several studies have shown a strong association between elevated plasma fibrinogen levels and risk of ischemic heart disease.^{1 2 3 4 5 6 7 10 11 12} A role for increased plasma fibrinogen levels has been also described in the risk for peripheral artery disease,⁹ mortality associated with peripheral artery disease, and graft occlusion after femoropopliteal vein bypass. Presently, the main concern about fibrinogen as a risk factor is whether the increase in fibrinogen simply reflects the atherothrombotic disease or whether it plays a causal role in its development. Our findings offer evidence of an active role of fibrinogen in cardiovascular disease, by demonstrating that a fibrinogen genotype, associated with higher fibrinogen levels, is independently associated with AMI. In this case, there is a genetic predisposition to have high levels of fibrinogen, which in the presence of an interactive condition, such as inflammation, predisposes the subject to develop AMI.

The number of B2B2 subjects in our AMI sample was smaller than that expected from the Hardy-Weinberg equilibrium. This could be due to a particular severity of the disease in such patients that predisposes to early fatal events. However, prospective studies are required to support such a hypothesis.

We selected patients with a family history of ischemic vascular disease, because genetic variants related to thrombosis development should be found more frequently in such patients than in those without a family history. The strong correlation between the increase in the B2 allele and familial AMI suggests the possible inheritance of the disease: it is conceivable that the transmission of the B2 allele, in combination with other risk factors for AMI, may account for its development in families.

Only 30% of all ischemic cardiovascular events can be predicted on the basis of established risk factors like hypercholesterolemia, smoking, overweight, diabetes, age, gender, and hypertension.²⁷ Although many of these factors have been related to myocardial infarction, in our study, the impact of the B2 allele on AMI risk was independent from them. On the other hand, the distribution of genetic polymorphisms can be more strongly influenced by the geographic and ethnic origin of the subjects under study than by the conventional factors related to AMI. The subjects participating in this study were all Italian and were homogeneously distributed throughout the main Italian geographic areas. Moreover, the catchment areas for cases and control subjects were comparable.

The finding that the B2 allele of the Bcl I fibrinogen polymorphism is a risk factor for familial AMI is in agreement with those of the Edinburgh Artery Study,⁹ which reported a higher frequency of the B2 allele in patients with peripheral artery disease than in control subjects. However, they did not find any correlation between the polymorphism and blood fibrinogen levels, either in patients or in control subjects. More recently Behague et al¹⁷ showed an association between genetic variants of the ß-fibrinogen locus and the severity of coronary artery disease in patients with AMI. However, they failed to demonstrate a clear association between the same alleles and AMI: only patients with a more severe coronary artery disease differed from control subjects in B2 allele distribution. It is therefore conceivable that this polymorphism could play a role (not yet defined) in the complex interactions between fibrinogen and atherosclerotic plaque evolution.^{28 29 30} We studied patients with a family history of thrombosis, which is considered by itself an independent risk factor for AMI^{11 24 31 32} and could overexpress the noxious effect of other risk factors with a potential genetic component such as hypertension, hyperlipidemia, or diabetes. In such a condition, the "multiple risk factor" theory³³ for disease implies that certain factors interact cumulatively to create high risk individuals with a particularly severe form of the disease.

High fibrinogen levels could be the candidate factor mediating the unfavorable effect of genetic predisposition linked to B2 allele on coronary atherosclerosis and thrombosis.^{9 34} This supposition could be confirmed by the marked difference in mean fibrinogen levels we found between AMI patients and control subjects carrying the B1B1 genotype versus those with the (B1B2+B2B2) genotype. Subjects carrying the B2 allele showed much higher fibrinogen levels than those carrying the B1 allele, after adjustment for smoking habits. In a stepwise regression analysis, the Bcl I polymorphism accounted for 14% and 8% of the total variance of plasma fibrinogen levels, respectively, in cases and control subjects. If the B1/B2 site was related to fibrinogen levels through the response of fibrinogen to stimuli, such as inflammation, then one would expect the difference between cases and control subjects in B2 subjects to be greater than the difference between cases and control subjects in B1 subjects. This appears, indeed, to be the case. Plasma fibrinogen levels were significantly different between AMI and control subjects, a difference mainly ascribed to the (B1B2+B2B2) genotype. Indeed, a formal analysis of interaction between genotype and fibrinogen levels showed that the difference in fibrinogen levels between cases and control subjects was significantly greater in (B1B2+B2B2) subjects than in subjects with the B1B1 genotype. Moreover, the association between the fibrinogen genotype and the risk of familial AMI was lost after correction in a multivariate analysis adjusted for the fibrinogen levels. These observations suggest that, in subjects with a family history of thrombosis, the influence of the genotype on the risk of AMI is at least in part due to its effect on fibrinogen levels.

Each polypeptide chain of fibrinogen is encoded by a separate mRNA, transcribed by three distinct, single-copy genes that cluster in about 50 kb on the distal third of the long arm of chromosome 4,^{4 19 20 35} where fibrinogen genes are organized in the order of: --ß. The rate-limiting step in the assembly of plasma fibrinogen is the synthesis of the ß chain.²² Therefore, it is conceivable that mutations in this gene could modulate the levels of fibrinogen, thus increasing the risk associated with high fibrinogen levels. We studied a polymorphism of the ß-chain gene, located in the 3' flanking region downstream of the -chain gene. This region does not possess well-defined properties but could contain regulatory sequences for mRNA synthesis. On the other hand, it could be only a marker for functional variants in the codifying regions or in the promoter that affect the sequence or the synthesis of the protein. The correlation between the population data reported here and their functional meaning, therefore, warrants further investigation.

Our study adds a new piece in the complex puzzle of factors which contribute to the risk of arterial thrombotic events. The OR associated with the B2 allele is comparable to those of hypertension, diabetes, and smoking status, although smaller than history of hyperlipidemia.

In conclusion, the novelty of the present work resides in the indication that in a population such as that with familial AMI, a link was found between (1) a genetic polymorphism of the fibrinogen gene, (2) the corresponding plasma levels of fibrinogen, and (3) the risk for a clinical event (AMI), three stages which had not been related so far in the same population. This link offers evidence for a causal role of fibrinogen in AMI and the basis for evaluating possible interventions to reduce fibrinogen levels in the prevention of this disease.

	Appendix 1

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Participating clinical centers. Asti (M. Alciati), Avellino (G. Amoroso), Barletta (A.M. Messina), Bologna "Sant'Orsola" (G. Palareti), Bozzolo (E. Franzì), Cagliari General Hospital (M. Sias), University of Cagliari Medical School (F. Marongiu), Casale Monferrato (M. Pezzana), Casarano (S. Ciricugno), Caserta (R. Di Sarno), Cento (L. Orselli), Colleferro (E. Venturini), Copertino (A. Calcagnile), Desio (G. Iacuitti), Fidenza (S. Callegari), Grosseto (A. Cresti), Guastalla (V. Manicardi), Lanciano (A. Valerio), Legnago (P. Todesco), Leno (A. Lanzini), Lodi (C. Pezzi), Lugo (T. Tognoli), Magenta (R. Turato), Mantova (A. Izzo), Mestre (G. Gasparini), Milano "Niguarda" (C. Corsini), Milano "Sacco" (E .Rossi), Mirano (A. Zanocco), Monza (F. Achilli), Napoli "Cardarelli" (F. Piantadosi), Napoli Second University (D. De Lucia), Novi Ligure (L. Fascioli), Nuoro (G. Tupponi), Palermo "Cervello" (A. Ledda, I. Greco), Palermo "Benfratelli" (R.G. La Malfa), Perugia (S. Brando), Pescara (T. Bonfini), Pescia (L. Iacopetti), Piombino (S. Bechi), Pisa (U. Conti), Rieti (S. Orazi), Rimini (F. Bologna), Roma "Policlinico" (P. De Paolis), San Donà di Piave (P. Della Valentina), San Giovanni Rotondo (A. Villella), Savona (A. Gandolfo), Termoli (M. Esposito), Torino "Maria Vittoria" (L. Mussano), Treviso (S. Perissinotto), Udine (G. Feruglio, C. Fresco), Vasto (E. Bottari), and Veruno (F. Soffiantino).

	Acknowledgments

 
This study was partially supported by the Italian National Research Council (Progetto Finalizzato FATMA, contract No. 95.00951.41). Francesco Zito is a recipient of a fellowship by Banca di Roma, Italy. This work was performed by Licia Iacoviello in partial fulfillment of the PhD thesis requirements of the University of Leiden (Prof B. Brakman). The authors wish to thank their colleagues of the GISSI-2 scientific committee, who shared the initial plannning of the study for helpful suggestions and Maria Pia De Simone for valuable assistance in the English editing of the manuscript.

Received January 14, 1997; accepted April 4, 1997.

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